One of the key questions in cognitive neuroscience is how the brain constructs and stores long-term memories of autobiographical events. The critical brain structures in this process are the hippocampus and surrounding regions of the medial temporal lobe. Despite decades of intensive research, the precise circuit mechanisms and computations performed by the hippocampus remain unclear. Although much is known about the representations encoded by the hippocampus proper, one of the major impediments has been a lack of detailed knowledge of the properties of the two major cortical inputs to the hippocampus, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). A major breakthrough occurred a few years ago when the "grid cell" was discovered in the MEC, providing the first firm handle on the representations encoded in this hippocampal afferent and a basis for beginning to understand the computations involved in transforming hippocampal afferent representations into its output representations. At the same time, our laboratory reported that LEC neurons displayed little spatial firing. Perhaps the most critical piece of information presently missing in our systems-level understanding of hippocampal processing is an elucidation of what is represented in the LEC. LEC cells are active when the rat investigates individual objects in an environment. The present proposal seeks to investigate in greater depth the nature of the representations of such external stimuli encoded by the LEC and how these representations become incorporated into the hippocampal place cell representation. We will use multiple tetrode arrays to record from populations of LEC, MEC, and CA1, and CA3 neurons in behaving rats to investigate the nature of spatial and nonspatial processing in the superficial layers of the LEC (which send projections into the hippocampus) and the deep layers (which receive projections from the hippocampus). We will test the hypothesis that the LEC is selectively active when the rat is engaged in behaviors denoting active attention to its surroundings (such as head- scanning movements during pauses in locomotion) and the MEC is selectively active when the animal is engaged in exploratory movements through its environment. We will test whether CA1 and CA3 create new place cells at locations associated with the rat's head-scanning behavior, suggesting the incorporation of external information from LEC into the rat's internal spatial representation of its environment. Because the human medial temporal lobe is likely to have similar place and grid-like properties, these experiments will help lay the foundation for understanding human learning and memory, which is critical for developing therapies for amnesic individuals that suffer from the devastating memory loss associated with such disorders as Alzheimer's Disease, temporal lobe epilepsy, and stroke. PUBLIC HEALTH RELEVANCE: Profound memory loss is a hallmark of such degenerative brain disorders as Alzheimer's Disease, which originates in an area called the entorhinal cortex, progresses into the hippocampus, and eventually progresses throughout the brain's cortical regions. The experiments in this proposal will address fundamental issues regarding the nature of information processing and functions in the entorhinal cortex and hippocampus, generating insight into how these brain regions work normally and how they may go awry when the regions are damaged by Alzheimer's disease, epilepsy, stroke, or traumatic injury.